The invention relates to antagonists of adenosine receptors and methods of making and using the same in the treatment of diseases.
Adenosine is an intracellular and extracellular messenger generated by all cells in the body. It is also generated extracellularly by enzymatic conversion. Adenosine binds to and activates seven transmembrane g-protein coupled receptors, eliciting a variety of physiological responses. Adenosine itself, substances that mimic the actions of adenosine (agonists), and substances that antagonize its actions have important clinical applications. Adenosine receptors are divided into four known subtypes (i.e., A1, A2a, A2b, and A3). These subtypes elicit unique and sometimes opposing effects. Activation of the adenosine A1 receptor, for example, elicits an increase in renal vascular resistance while activation of the adenosine A2a receptor elicits a decrease in renal vascular resistance.
In most organ systems, periods of metabolic stress result in significant increases in the concentration of adenosine in the tissue. The heart, for instance, produces and releases adenosine to mediate adaptive responses to stress, such as reductions in heart rate and coronary vasodilatation. Likewise, adenosine concentrations in kidneys increase in response to hypoxia, metabolic stress and many nephrotoxic substances. The kidneys also produce adenosine constitutively. The kidneys adjust the amount of constitutively produced adenosine in order to regulate glomerular filtration and electrolyte reabsorption. Regarding control of glomerular filtration, activation of A1 receptors leads to constriction of afferent arterioles while activation of A2a receptors leads to dilatation of efferent arterioles. Activation of A2a receptors may also exert vasodilatory effects on the afferent arteriole. Overall, the effect of activation of these glomerular adenosine receptors is to reduce glomerular filtration rate. In addition, A1 adenosine receptors are located in the proximal tubule and distal tubular sites. Activation of these receptors stimulates sodium reabsorption from the tubular lumen. Accordingly, blocking the effects of adenosine on these receptors will produce a rise in glomerular filtration rate and an increase in sodium excretion.
The invention is based on the discovery that compounds of Formula I are unexpectedly highly potent and selective inhibitors of particular subtypes of adenosine receptors. Adenosine antagonists can be useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable.
In one embodiment, the invention features a compound of formula (I): 
where
R1 and R2 are independently chosen from: (a) hydrogen; (b) alkyl, alkenyl of not less than 3 carbons, or alkynyl of not less than 3 carbons; wherein the alkyl, alkenyl, or alkynyl is either unsubstituted or functionalized with one or two substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and (c) aryl and substituted aryl.
R3 is a bicyclic or tricyclic group chosen from: 
where the bicyclic or tricyclic group can be unsubstituted or can be functionalized with one or more (e.g., one, two, three, or more) substituents chosen from: (a) alkyl, alkenyl, and alkynyl; wherein the alkyl, alkenyl, and alkynyl are either unsubstituted or functionalized with one or more substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylaminoalkylamino, aralkoxycarbonyl, xe2x80x94R5, dialkylamino, heterocyclylalkylamino, hydroxy, substituted arylsulfonylaminoalkylamino, and substituted heterocyclylaminoalkylamino; (b) acylaminoalkylamino, alkenylamino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoacyloxy, alkoxycarbonylaminoalkylamino, alkylamino, amino, aminoacyloxy, carbonyl, xe2x80x94R5, R5-alkoxy, R5-alkylamino, dialkylaminoalkylamino, heterocyclyl, heterocyclylalkylamino, hydroxy, phosphate, substituted arylsulfonylaminoalkylamino, substituted heterocyclyl, and substituted heterocyclylaminoalkylamino.
R4 is chosen from xe2x80x94H, xe2x80x94C1-4-alkyl, xe2x80x94C1-4-alkyl-CO2H, and phenyl; and can be unsubstituted or can be functionalized with one or more substituents chosen from halogen, xe2x80x94OH, xe2x80x94OMe, xe2x80x94NH2, xe2x80x94NO2 and benzyl, optionally substituted with one, two, or three groups selected from halogen, xe2x80x94OH, xe2x80x94OMe, xe2x80x94NH2, and xe2x80x94NO2.
R5 is chosen from xe2x80x94CH2COOH, xe2x80x94C(CF3)2OH, xe2x80x94CONHNHSO2CF3, xe2x80x94CONHOR4, xe2x80x94CONHSO2R4, xe2x80x94CONHSO2NHR4, xe2x80x94C(OH)R4PO3H2, xe2x80x94NHCOCF3, xe2x80x94NHCONHSO2R4, xe2x80x94NHPO3H2, xe2x80x94NHSO2R4, xe2x80x94NHSO2NHCOR4, xe2x80x94OPO3H2, xe2x80x94OSO3H, xe2x80x94PO(OH)R4, xe2x80x94PO3H2, xe2x80x94SO3H, xe2x80x94SO2NHR4, xe2x80x94SO3NHCOR4, xe2x80x94SO3NHCONHCO2R4, and the following: 
X1 and X2 are chosen, independently, from oxygen (O) and sulfur (S).
Z is chosen from a single bond, xe2x80x94Oxe2x80x94, xe2x80x94(CH2)1-3xe2x80x94, xe2x80x94O(CH2)1-2xe2x80x94, CH2OCH2xe2x80x94, xe2x80x94(CH2)1-2Oxe2x80x94, and xe2x80x94CH2CHxe2x95x90CHxe2x80x94.
R6 is chosen from hydrogen, alkyl, acyl, alkylsufonyl, aralkyl, substituted aralkyl, substituted alkyl, and heterocyclyl.
R6 is preferably hydrogen. However, when R6 is methyl or another non-hydrogen substituent, the compounds can be highly selective for inhibition of adenosine A2a receptors.
In certain embodiments, R1 and R2 can be the same or different alkyl groups. For example, one or both can be n-propyl.
In some embodiments, Z is a single bond.
In one embodiment, R3 is chosen from the following bicyclic and tricyclic structures: 
and is functionalized with one or more substituents chosen from carbonyl, hydroxy, alkenyl, alkenyloxy, hydroxyalkyl, carboxy, carboxyalkenyl, carboxyalkyl, aminoacyloxy, carboxyalkoxy, dialkylaminoalkenyl, and dialkylaminoalkyl.
In another embodiment, R3 is: 
and is functionalized with one or more substituents chosen from carbonyl, hydroxy, alkenyl, carboxyalkenyl, hydroxyalkyl, dialkylaminoalkenyl, and dialkylaminoalkyl. Thus, for example, the compound can be 8-(5-Hydroxy-tricyclo[2.2.1.02,6]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; 8-(5-Hydroxymethyl-tricyclo[2.2.1.02,6]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; 8-[5-(3-Dimethylaminopropylidene)-tricyclo[2.2.1.02,6]hept-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; or 8-[5-(3-Dimethylaminopropyl)-tricyclo[2.2.1.02,6]hept-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.
In still another embodiment, R3 is: 
and is functionalized with one or more substituents chosen from hydroxy, carbonyl, alkyl, xe2x80x94R5, R5-alkyl, dialkylaminoalkylamino, alkoxycarbonylalkylamino, R5-alkylamino, heterocyclyl, alkenylamino, amino, alkylamino, heterocyclylalkylamino, acylaminoalkylamino, phosphate, heterocyclylaminoalkylamino, and heterocyclylaminoalkylaminoalkyl.
In yet another embodiment, R3 is: 
and is functionalized with one or more substituents chosen from hydroxy, xe2x80x94R5, R5-alkyl, and hydroxyalkyl. Thus, for example, the compound can be 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carboxylic acid.
In another embodiment, R3 is: 
and is functionalized with one or more substituents chosen from alkyl, hydroxy, carbonyl, xe2x80x94R5, and R5-alkyl. Thus, for example, the compound can be 8-(4-Hydroxy-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; or 8-(4-Oxo-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.
In still another embodiment, R3 is: 
and is functionalized with one or more substituents chosen from carbonyl, hydroxy, dialkylaminoalkylamino, xe2x80x94R5, and substituted heterocyclylaminoalkylaminoalkyl. Thus, for example, the compound can be 8-[8-(2-Dimethylaminoethylamino)-bicyclo[3.2.1]oct-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; or 8-(8-Hydroxy-bicyclo[3.2.1]oct-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.
In yet another embodiment, R3 is: 
and is functionalized with one or more substituents chosen from carbonyl, hydroxy, and xe2x80x94R5. Thus, for example, the compound can be 8-(3-Hydroxy-bicyclo[3.2.1]oct-8-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.
In yet another embodiment, R3 is selected from bicycles: 
and is functionalized with one or more substituents chosen from hydroxyalkyl, hydroxy, and alkoxycarbonyl. Thus, for example, the compound can be 8-(8-Oxa-bicyclo[3.2.1]oct-6-en-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.
In yet another embodiment, R3 is: 
and is functionalized with one or more substituents chosen from carbonyl, aralkyloxycarbonylalkyl, and alkoxycarbonylalkyl. Thus, for example, the compound can be 8-(2-Oxo-3-aza-bicyclo[3.2.1]oct-8-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.
The compound can be, for example, in a form of an achiral compound, a racemate, an optically active compound, a pure diastereomer, a mixture of diastereomers, or a pharmacologically acceptable addition salt.
The compounds of this invention can also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and/or alter rate of excretion. Examples of these modifications include, but are not limited to, esterification with polyethylene glycols, derivatization with pivolates or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings, and heteroatom-substitution in aromatic rings.
The invention also features a medicament composition including any of the above compounds, alone or in a combination, together with a suitable excipient.
The invention also features a method of treating a subject suffering from a condition characterized by an elevated adenosine concentration and/or increased sensitivity to adenosine and/or elevated adenosine receptor number or coupling efficiency. The method includes the step of administering to the subject an amount of any of the above compounds to be effective as an adenosine A1 receptor antagonist. The condition can be, for example, a cardiac and circulatory disorder, a degenerative disorder of the central nervous system, a respiratory disorder, a disease for which diuretic treatment is indicated, hypertension, Parkinson""s disease, depression, traumatic brain damage, post-stroke neurological deficit, respiratory depression, neonatal brain trauma, dyslexia, hyperactivity, cystic fibrosis, cirrhotic ascites, neonatal apnea, renal failure, diabetes, asthma, an edematous condition, congestive heart failure, or renal dysfunction associated with diuretic use in congestive heart failure.
The invention also features a method of making 8-substituted xanthines. The method includes the steps of obtaining a N7,C8-dihydroxanthine, protecting the N7 position of the xanthine (e.g., as a THP or BOM ether); deprotonating the C8 position with strong base (such as lithium di-isopropyl amide or n-butyl lithium) to generate an anion; trapping the anion with a carboxyl, carbonyl, aldehyde, or ketone compound; and deprotecting the protected N7 position to obtain an 8-substituted xanthine.
As used herein, an xe2x80x9calkylxe2x80x9d group is a saturated aliphatic hydrocarbon group. An alkyl group can be straight or branched, and can have, for example, from 1 to 6 carbon atoms in a chain. Examples of straight chain alkyl groups include, but are not limited to, ethyl and butyl. Examples of branched alkyl groups include, but are not limited to, isopropyl and t-butyl.
An xe2x80x9calkenylxe2x80x9d group is an aliphatic carbon group that has at least one double bond. An alkenyl group can be straight or branched, and can have, for example, from 3 to 6 carbon atoms in a chain and 1 or 2 double bonds. Examples of alkenyl groups include, but are not limited to, allyl and isoprenyl.
An xe2x80x9calkynylxe2x80x9d group is an aliphatic carbon group that has at least one triple bond. An alkynyl group can be straight or branched, and can have, for example, from 3 to 6 carbon atoms in a chain and 1 to 2 triple bonds. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl.
An xe2x80x9carylxe2x80x9d group is a phenyl or naphthyl group, or a derivative thereof. A xe2x80x9csubstituted arylxe2x80x9d group is an aryl group that is substituted with one or more substituents such as alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkylamino, dialkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, trihaloalkyl, carboxyalkyl, sulfoxy, or carbamoyl.
An xe2x80x9caralkylxe2x80x9d group is an alkyl group that is substituted with an aryl group. An example of an aralkyl group is benzyl.
A xe2x80x9ccycloalkylxe2x80x9d group is an aliphatic ring of, for example, 3 to 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl and cyclohexyl.
An xe2x80x9cacylxe2x80x9d group is a straight or branched alkyl-C(xe2x95x90O)xe2x80x94 group or a formyl group. Examples of acyl groups include alkanoyl groups (e.g., having from 1 to 6 carbon atoms in the alkyl group). Acetyl and pivaloyl are examples of acyl groups. Acyl groups may be substituted or unsubstituted.
A xe2x80x9ccarbamoylxe2x80x9d group is a group having the structure H2Nxe2x80x94CO2xe2x80x94. xe2x80x9cAlkylcarbamoylxe2x80x9d and xe2x80x9cdialkylcarbamoylxe2x80x9d refer to carbamoyl groups in which the nitrogen has one or two alkyl groups attached in place of the hydrogens, respectively. By analogy, xe2x80x9carylcarbamoylxe2x80x9d and xe2x80x9carylalkylcarbamoylxe2x80x9d groups include an aryl group in place of one of the hydrogens and, in the latter case, an alkyl group in place of the second hydrogen.
A xe2x80x9ccarboxylxe2x80x9d group is a xe2x80x94COOH group.
An xe2x80x9calkoxyxe2x80x9d group is an alkyl-Oxe2x80x94 group in which xe2x80x9calkylxe2x80x9d is as previously described.
An xe2x80x9calkoxyalkylxe2x80x9d group is an alkyl group as previously described, with a hydrogen replaced by an alkoxy group, as previously described.
A xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d group is fluorine, chlorine, bromine or iodine.
A xe2x80x9cheterocyclylxe2x80x9d group is a 5 to about 10 membered ring structure, in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O, S. A heterocyclyl group can be aromatic or non-aromatic, i.e., can be saturated, or can be partially or fully unsaturated. Examples of heterocyclyl groups include pyridyl, imidazolyl, furanyl, thienyl, thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, indolyl, indolinyl, isoindolinyl, piperidinyl, pyrimidinyl, piperazinyl, isoxazolyl, isoxazolidinyl, tetrazolyl, and benzimidazolyl.
A xe2x80x9csubstituted heterocyclylxe2x80x9d group is a heterocyclyl group wherein one or more hydrogens are replaced by substituents such as alkoxy, alkylamino, dialkylamino, carbalkoxy, carbamoyl, cyano, halo, trihalomethyl, hydroxy, carbonyl, thiocarbonyl, hydroxyalkyl or nitro.
A xe2x80x9chydroxyalkylxe2x80x9d means an alkyl group substituted by a hydroxy group.
A xe2x80x9csulfamoylxe2x80x9d group has the structure xe2x80x94S(O)2NH2. xe2x80x9cAlkylsulfamoylxe2x80x9d and xe2x80x9cdialkylsulfamoylxe2x80x9d refer to sulfamoyl groups in which the nitrogen has one or two alkyl groups attached in place of the hydrogens, respectively. By analogy, xe2x80x9carylsulfamoylxe2x80x9d and xe2x80x9carylalkylsulfamoylxe2x80x9d groups include an aryl group in place of one of the hydrogens and, in the latter case, an alkyl group in place of the second hydrogen.
An xe2x80x9cantagonistxe2x80x9d is a molecule that binds to a receptor without activating the receptor. It competes with the endogenous ligand for this binding site and, thus, reduces the ability of the endogenous ligand to stimulate the receptor.
In the context of the present invention, a xe2x80x9cselective antagonistxe2x80x9d is an antagonist that binds to a specific subtype of adenosine receptor with higher affinity than to other subtypes. The antagonists of the invention can, for example, have high affinity for A1 receptors or for A2a receptors and are selective, having (a) nanomolar binding affinity for one of these two subtypes and (b) at least 10 times, more preferably 50 times, and most preferably at least 100 times, greater affinity for one subtype than for the other.
The invention provides numerous advantages. The compounds are easily manufactured from readily available starting materials, in a relatively small number of steps. The compounds have a number of variable regions, allowing for systematic optimization. As A1-specific antagonists, the compounds have broad medicinal utility. Since the compounds are highly potent and specific A1 antagonists, they can (1) be used in low doses to minimize the likelihood of side effects and (2) be incorporated into numerous dosage forms including, but not limited to, pills, tablets, capsules, aerosols, suppositories, liquid formulations for ingestion or injection, dietary supplements, or topical preparations. In addition to medical applications, the antagonist compound can be used in the treatment of livestock and pet animals.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.